The present invention relates to substituted spiroamines, processes for the preparation thereof, medicaments containing these compounds and the use of substituted spiroamines in pharmaceutical compositions and for the treatment of pain and other conditions mediated by the bradykinin 1 receptor (B1R).
In contrast to the constitutive expression of the bradykinin 2 receptor (B2R), the bradykinin 1 receptor is not expressed or is only weakly expressed in most tissues. Nevertheless, expression of the B1R can be induced on various cells. By way of example, in the course of inflammation reactions a rapid and pronounced induction of the B1R takes place on neuronal cells, but also on various peripheral cells, such as fibroblasts, endothelial cells, granulocytes, macrophages and lymphocytes. Thus, in the course of inflammation reactions a switch from a B2R to a B1R dominance occurs on the cells involved. The cytokines interleukin-1 (IL-1) and tumour necrosis factor alpha (TNFα) are substantially involved in this B1R up-regulation (Passos et al. J. Immunol. 2004, 172, 1839-1847). After activation with specific ligands, B1R-expressing cells can subsequently themselves secrete inflammation-promoting cytokines, such as IL-6 and IL-8 (Hayashi et al., Eur. Respir. J. 2000, 16, 452-458). This leads to inwards migration of further inflammation cells, for example neutrophilic granulocytes (Pesquero et al., PNAS 2000, 97, 8140-8145). The bradykinin B1R system can contribute to the chronification of diseases via these mechanisms. This is demonstrated by a large number of animal studies (overviews in Leeb-Lundberg et al., Pharmacol Rev. 2005, 57, 27-77 and Pesquero et al., Biol. Chem. 2006, 387, 119-126). In humans too, an increased expression of the B1R is seen, for example on enterocytes and macrophages in the affected tissue of patients with inflammatory bowel diseases (Stadnicki et al., Am. J. Physiol. Gastrointest. Liver Physiol. 2005, 289, G361-366) and on T lymphocytes of patients with multiple sclerosis (Prat et al., Neurology. 1999; 53, 2087-2092), or an activation of the bradykinin B2R-B1R system is seen in the course of infections with Staphylococcus aureus (Bengtson et al., Blood 2006, 108, 2055-2063). Infections with Staphylococcus aureus are responsible for disease profiles such as superficial infections of the skin through to septic shock.
Based on the pathophysiological relationships described, there is great therapeutic potential for the use of B1R antagonists against acute and in particular chronic inflammatory diseases. They include diseases of the respiratory tract (bronchial asthma, allergies, COPD/chronic obstructive pulmonary disease, cystic fibrosis, etc.), inflammatory bowel diseases (ulcerative colitis, CD/Crohn's disease, etc.), neurological diseases (multiple sclerosis, neurodegeneration, etc.), inflammations of the skin (atopic dermatitis, psoriasis, bacterial infections, etc.) and mucous membranes (Behcet's disease, chronic pelvic pain, prostatitis, etc.), rheumatic diseases (rheumatoid arthritis, osteoarthritis, etc.), septic shock and reperfusion syndrome (following heart attack or stroke).
The bradykinin (receptor) system is moreover also involved in the regulation of angiogenesis (potential as an angiogenesis inhibitor in cases of cancer and macula degeneration in the eye), and B1R-knockout mice are protected from the induction of obesity by a particularly high-fat diet (Pesquero et al., Biol. Chem. 2006, 387, 119-126). B1R antagonists are therefore also suitable for the treatment of obesity.
B1R antagonists are particularly suitable for the treatment of pain, in particular inflammatory pain and neuropathic pain (Calixto et al., Br. J. Pharmacol 2004, 1-16), and here in particular diabetic neuropathy (Gabra et al., Biol. Chem. 2006, 387, 127-143). They are also suitable for the treatment of migraine.
In the development of B1R modulators there is the problem, however, that the human and the rat B1R receptor differ so widely that many compounds which are good B1R modulators on the human receptor have only a poor or no affinity for the rat receptor. This makes animal pharmacology studies considerably more difficult, since many studies are usually conducted on the rat. However, if there is no activity on the rat receptor, neither action nor side-effect can be investigated on the rat. This has already meant that transgenic animals with human B1 receptors have been produced for animal pharmacology studies (Hess et al., Biol. Chem. 2006; 387(2):195-201). Working with transgenic animals is, however, more expensive than working with the unmodified animals.
The patent applications WO 2007/140383 and WO 2007/101007 describe compounds which in in-vitro assays exhibit an antagonistic action on the macaque B1 receptor. Experimental data on the activity on the human B1 receptor or the B1 receptor of the rat is not disclosed.
Published US patent application nos. US 2008/153843 (=WO 2008/040492) and US 2008/249128 (=WO 2008/046573) describe compounds which in in-vitro assays exhibit an antagonistic action on both the human and the rat B1 receptors.
However, there remains a need for novel B1R modulators, and particularly for B1R modulators which bind both to the rat receptor and to the human receptor.